what will you (and i) do on...

What Will You (and I) do on Monday

Sanjiv S. Agarwala, MD Professor of Medicine, Temple University

Chief, Oncology & Hematology St. Luke’s Cancer Center, Bethlehem, PA

Disclosures

• Consultant: Bristol-Myers Squibb; Genentech; Merck & Co., Inc.

• Fees for Non-CME Services: Bristol-Myers Squibb; Genentech; Merck Co., Inc .

Session 1 Dermatology

Surveillance Technologies:

Challenges (Marghoob)

1. Find concerning lesions: difficulty finding

biologically relevant (new/changing) lesions

in patients with many nevi / atypical nevi.

2. Diagnosing concerning lesion: clinical

diagnostic accuracy (reflected by B:M ratio)

remains less than ideal.

3. Rapidly growing melanomas are escaping

early detection.

Risks of indoor tanning (Halpern)

Lim et al. J Am Acad Dermatol. 2011 Apr;64(4):e51-60

Melanoma Risk Alleles (Tsao) Sporadic

Familial

CDKN2A CDK4 XP Unknown

Summary from Session 1

• The technology to pick up and diagnose melanomas and other skin cancers is improving

• Dermoscopy should be standard • Tanning beds are bad for you • Screening is feasible in a large population and

may reduce mortality (50%) – Cost – Government controls

• Genetics of melanoma is complicated – Send your patients to Dr Tsao

Session 2 Surgery and Adjuvant Therapy

SLN VALUE AS A STAGING

PROCEDURE (Balch)

• Most accurate, reproducible and cost-effective test

available today for regional node micrometastases

• Staging value:

– Used for patient selection of complete node

dissection

– Used for patient selection of adjuvant systemic

therapy , especially interferon therapy

– Imperative for entry into melanoma clinical trials

Debate:

ASCO/SSO Guidelines for SLNB

Do they represent the gold

standard?

Department of Cutaneous Oncology

• Sentinel node biopsy widely accepted

worldwide, but indications in thin melanomas

and role of CLND, especially for small-

volume nodal disease and for positive in

transit nodes, remains controversial

• The ASCO/SSO guidelines add an important

degree of objective support for the

procedure, but are not the “Gold Standard”

Clearly our patients require personalized care

Are the ASCO/SSO Evidence Based Guidelines for

Sentinel Node Biopsy the Gold Standard?

S-0008 Summary/Conclusions

(Flaherty)

1) BCT is the first and only therapy to demonstrate a statistically significant improvement in RFS compared to HD-IFN in high-risk stage III melanoma pts;

2) BCT was not associated with any improvement in OS compared to HD-IFN in high-risk stage III melanoma pts

3) Without a significant OS benefit, BCT does not replace IFN as a standard of care

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10

Years from registration

Surv

ival pro

ba

bility

HDI

BCT

203 155 114 70 32 4

199 144 111 63 29 5

N at risk

HDI

BCT

HR = 1.02, 95% CI = (0.76, 1.37)

Two−sided p = 0.88, one−sided p = 0.56

Median: HDI = 8.42 years, BCT = Not reached

5−year OS: HDI = 56%, BCT = 56%

Overall survival

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10

Years from registration

Surv

ival pro

ba

bility

HDI

BCT

203 95 77 49 24 3

199 108 93 53 25 5

N at risk

HDI

BCT

HR = 0.76, 95% CI = (0.58, 0.98)

Two−sided p = 0.034, one−sided p = 0.017

Median: HDI = 1.90 years, BCT = 4.31 years

5−year OS: HDI = 39%, BCT = 47%

Progression−free survival

Debate: Interferon Sensitivity

Adjuvant IFN should only be used in patients with ulceration and/or

microscopic disease

p=0.006 HR=0.59 (99% CI 0.35 , 0.97)

Median OS: 3.7 yrs vs > 8 yrs

(years)

0 2 4 6 8 10

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :

61 90 68 41 32 6

46 96 78 57 51 16

Observation

Peg-IFN alfa

Peg-IFN:III-N1 & Ulceration:

OVERALL SURVIVAL

------------------------------------------------------------------------------------------------------------

x

7.6 YEARS F.U.


• Random chance – a statistical “lie”

• Ulceration is a marker of poor prognosis

(ie, more “events”), so there may be more

power to see a statistical impact

• Maybe peg-IFN is way better than regular

IFN, with a dramatic impact on survival

o Then why didn’t we see this impact in the overall

trial results (ie, why didn’t the palpable node

subset also benefit)?

ADJUVANT INTERFERON FOR MELANOMA

Is there an alternate explanation for the large

apparent subset benefit in EORTC 18991?

Session 2: Summary

• SLNB is an important staging procedure that provides crucial prognostic information

• The exact population who should receive SLNB is not completely defined but the ASCO/SSO guideline is a good guide

• Biochemotherapy improves RFS (but not OS) as compared to IFN. It is an option but does not replace IFN

• Interferon sensitivity is an interesting concept but needs to be validated in prospective trials – Ulcerated/microscopic+ nodes had greatest benefit in PEG

IFN trial

Session 3 Local-Regional Therapy

Intralesional agents in the era of

ipilimumab and vemurafenib

• Combination therapies may improve response:

– Anti-CTLA-4 + intralesional agent

– PD-1 + intralesional agent

– B-raf inhibitors + intralesional agent

– 2 consecutive intralesional agents

– HD IL-2 + intralesional agent

– Intralesional agent + radiation

http://www.hci.utah.edu/index.jsp

Likely indications for intralesional therapy?

• Only BCG and IL-2 currently available

• Phase III Allovectin-7 and T-VEC

• results pending

• Probable indication:

– Cutaneous or nodal injectable lesions that are not

surgically curative (IIIB and IIIC)

– Low disease burden stage IV M1a, M1b disease

– Indication in M1c disease uncertain

– Patients with poorer performance status

• Not indicated in rapidly progressing disease

http://www.hci.utah.edu/index.jsp

Conclusions

• IL-12 plasmid electroporation is

associated with a tolerable side effect

profile

• Phase I

– Widespread local responses and 10%

systemic CR

• Phase II

– 2/13 Distant Responses

• 4/13 awaiting D180 eval

– 10/13 Local responses

Melanoma

Metastatic

to Liver

(n = 93)

PHP Arm

(n = 44)

BAC Arm (n = 49)

H

E

P

A

T

I

C

P

R

O

G

R

E

S

S

I

O

N

Cross over to PHP

(n=28, 57%)

Results: Randomization and Treatment Schema

-93 Patients at 10 Institutions-

R

A

N

D

O

M

I

Z

E

1:1

Follow-up

Follow-up

Total Accrual: 93 patients

(PHP: 44, BAC: 49, Crossover: 28)

Results: Primary Endpoint

-Hepatic Progression Free Survival (ITT) -

Hazard Ratio: 0.35

(CI: 0.23-0.54)

0 5 10 15 20 25 30 35

Time (months)

BAC

PHP

8.0 1.6

p<0.0001

1.0

Surv

ival pro

babili

ty

0.8

0.6

0.4

0.2

0.0

Session 3: Local-Regional Therapy Summary

• Melanoma is a systemic disease but local regional therapies may represent an important component of therapy – In combination with systemic Rx

– Poor PS, elderly patients

– Prior to systemic Rx to avoid toxicity

• Chemosaturation of the liver shows good results in terms of PFS – Uveal melanoma

Session 4 Clinical Conundrums

SURGERY FOR METASTATIC MELANOMA

NCCN Guidelines v1.2013

Limited (Resectable) Metastatic Disease

Resect or Observe or systemic therapy, then

repeat scans [duration not specified], if

negative for other disease then resect

Evidence-based guidelines for when and how

long potentially resectable patients should be

observed or treated, and whether this strategy of

deferring surgery improves outcomes or

decreases morbidity, are lacking at this time.


SURGERY FOR METASTATIC MELANOMA

Looking to the Future • Improved algorithms for following high-risk stage II

and III melanoma patients are needed to identify

patients most likely to benefit from metastasectomy

• Neoadjuvant therapy for BRAF mutant patients with

unresectable or borderline resectable tumors

• “Surgical gene therapy” for patients with multiple

metastases treated with targeted therapy in whom

most tumors are stable but one or two are growing

• Experience in GIST tumors treated with imatinib showed

benefit for eliminating these resistant tumors while

continuing effective therapy for the other metastases

Therapies that are Across the Goal-line

• BRAF Inhibition

• Anti-CTLA4 Antibody Therapy

Therapies that are in the Red Zone

• BRAF Inhibition plus MEK Inhibition

• Anti-PD1 Antibody Therapy

Therapies that are at the 50 Yard-line

• Adoptive T-cell Therapy

The Importance of Getting Therapies

Across the Goal-line (Hwu)

31

Clinical Response Data from MDACC

TIL ACT Clinical Trial (as of July 10, 2012)

Best overall response:

*Some patients are still undergoing clinical response

Number of

patients CR* PR* Total

51 2 (4%) 21(41%) 23 (45%)

32

Clin Cancer Res 18: 6758-6770, 2012

Radvanyi … Hwu

Session 4: Clinical Conundrums Summary

• Metastatectomy is an option for selected patients

• Data with newer agents in brain metastases in melanoma is exciting and promising

– Local therapy is still important

• Adoptive T-cell transfer is an interesting technology but for selected patients at select institutions

Session 5 Other Cutaneous Malignancies


Summary (Messina)

Atypical Spitz tumor: What does it mean

and how is it managed?

• Increasingly recognized melanocytic neoplasm

which deviates from typical benign Spitz but

does not seem to have a distinctive molecular or

genetic profile

• Most common in children and young adults

• Frequent but low-volume SLN metastasis

• Low recurrence rate with relatively long-term

followup

35


Summary (Messina)

Atypical Spitz tumor: What does it mean

and how is it managed?

• Workup should include expert consultation,

molecular analysis by FISH and/or CGH

• Recommend wide excision and SLN biopsy until

reliable test to exclude melanoma is available

Non-Melanomatous Skin Cancers

Objectives/Topics (Pfister)

• Squamous Cell

• Basal Cell

• Dermatofibrosarcoma Protuberans

• Merkel Cell

Vismodegib (GDC-0449)

Phase II

• Multicenter, international, two cohort (metastatic

and locally advanced basal cell cancer).

• 150 mg daily dosing

• Toxicity

– Muscle spasms, alopecia, dysgeusia, weight loss, fatigue

(>30%).

– SAEs in 25%; 7 deaths (relationship to study drug

unknown; felt unrelated to vismodegib by site

investigator).

• Independently assessed response

– Metastatic (n=33): 30%

– Locally advanced (n=63): 43% (21% CRs)

– Median duration 7.6 months (both cohorts)

N Engl J Med 2012;366:2171

Somatic BAP1 mutations in Cancer (Wiesner)

Primary tissue % Mutated Mutated samples Total samples

Uveal Melamoma 43.1 41 95

Mesothelioma 26.9 51 189

Clear Cell Renal Cell Carcinoma 13.0 58 446

Bladder Cancer 5.4 2 37

Cutanous Melanoma/AST 3.5 13 363

Endometrium Carcinoma 1.4 3 204

Lung Carcinoma 1.1 11 929

Prostate Cancer 1.0 4 376

Ovary Carcinoma 0.6 4 665

Breast Cancer 0.5 4 691

Colon Carcinoma 0.4 3 689

Session 6 Metastatic Melanoma

Immunotherapy

Kaplan-Meier Analysis of Survival

Years

Ipilimumab + gp100 (A)

Ipilimumab alone (B)

gp100 alone (C)

1 2 3 4

Comparison HR P-value

Arm A vs C 0.68 0.0004

Arm B vs C 0.66 0.0026

Arm A vs B 1.04 0.7575

Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone

1-year 44% 46% 25%

2-year 22% 24% 14%

Proportion

Alive

0. 0

0. 1

0. 2

0. 3

0. 4

0. 5

0. 6

0. 7

0. 8

0. 9

1. 0

Years

0 1 2 3 4

42

Study 024: Overall Survival

Estimated Survival Rate 1 Year 2 Year 3 Year*

Ipilimumab + DTIC

n=250 47.3 28.5 20.8

Placebo + DTIC

n=252 36.3 17.9 12.2

*3-year survival was a post-hoc analysis

Ipilimumab + DTIC

Placebo + DTIC

Summary (Wolchok)

• Checkpoint blockade is an effective treatment with durable responses.

• Intense study of both predictive and pharmacodynamic biomarkers of response and toxicity will allow for more intelligent patient selection and novel target discovery.

• New and promising immune modulators are in clinical development.

• Combination therapy will be necessary for immunotherapy to achieve full potential (other immune modulators, vaccines, radiation, chemotherapy, targeted therapy, anti-angiogenic therapy).

PD-1: Role in T Cell Activation

Member of CD28 family involved in T cell regulation

Expressed by activated T cells, memory T cells, and regulatory T cells

Downregulates T cell activity upon binding to PD-L1/L2

Tumor PD-L1 expression may correlate with negative prognosis potential mechanism of tumor self-defense

What is

PD-1?

PD-1 = programmed death-1. Curran MA et al. PNAS. 2010;107:4275-4280.

Changes in Target Lesions Over Time in

Melanoma Patients after BMS 936558

Hodi, S. et al ASCO 2012

Best Overall Response of MK-3475 (Unconfirmed +

Confirmed Responses) in Advanced MEL Patients

(Part B; based on immune related Response Criteria*)

Complete

Response

(N, 95% CI)

Objective Response

(N, 95% CI)

Disease Control

Rate

(N, 95% CI)

All MEL

N=85

9%

(8; 4% -18%)

51%

(43; 39 % -61%)

59%

(50; 48% -69%)

IPI Naïve

N=58

14%

(8; 6% -25%)

55%

(32; 41% -68%)

64%

(37; 50% -76%)

IPI Treated

N=27

0%

(0)

41%

(11; 22% -61%)

48%

(13; 29% -68%)

All patients were dosed at 10 mg/kg

Includes all patients who received first dose as of April 25, 2012.

Investigator reported response information as of October 19, 2012.

Objective response= confirmed and unconfirmed complete and partial response

Disease control rate= Objective response + stable disease

*irRC: Wolchok, JD, Hoos, A, O’Day S, et al., Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-

Related Response Criteria. Clinical Cancer Research, 2009 Dec 1;15(23):7412-20. Epub 2009 Nov 24)

Hamid, O et al SMR 2012

Maximum Percent Change from Baseline in Tumor

Burden by irRC (Central Review Part B)

% C

han

ge f

rom

Base

lin

e (s

um

of

lon

ges

t

dia

me

ters

)

Individual Patient

500

560

*0 % change in tumor burden

**Skin only disease (n=1) with complete regression

All patients are dosed at 10mg/kg

*

**

Hamid, O et al SMR 2012

Durable responses with HD IL-2

Atkins M et al., High-Dose Recombinant Interleukin 2 Therapy for Patients with Metastatic Melanoma: Analysis of 270 Patients Treated Between 1985 and 1993., J Clin Onc 17: 2105 (1999).

Eight Phase II clinical studies conducted at 22 institutions

Targeted Rx + IL-2 Inhibitors possess

high response rates but low cure

rates (if any)

Immunotherapy can cure but

have low response rates

Control MEK i BRAF i

100 Melanoma Differentiation Antigen Lymphocyte recognition within tumor Biopsy Study – Increased T4 infiltration of BRAFi tissues. Boni A, et al. 2010. Selective BRAF V600E inhibition enhances T-cell recognition of melanoma without

affecting lymphocyte function. Cancer Research 70:5213-5219

Session 6: Summary

• Ipilumumab shows an OS advantage in 2 randomized trials and is approved for use in metastatic/melanoma

• PD-1 may be the new and improved ipilimumab

• IL-2 is here to stay. An appropriate front line option for selected patients

• Combinations/sequencing remain critical questions

Session 7 Metastatic Melanoma

Targeting the Genome and the Blood Vessels

MAPK Pathway Growth

Factors

RAS

BRAF

MEK

ERK

Cell proliferation

and survival

Vemurafenib vs Dabrafenib –

Adverse Events AE grade vemurafenib dabrafenib

SCC/KA 2 2% 2%

3 18% 4%

Pyrexia 2 NR (<5%) 2%

3 3%

Photosensitivity Any grade 30% NR

Alopecia 2 8% 0%

Arthralgia 2 18% 5%

3 3% <1%

Hyperkeratosis 2 5% 12%

3 1% <1%

Nausea 2 7% 1%

3 1% 0%

Fatigue 2 11% 5%

3 2% 1%

Headache 2 4% 5%

3 <1% 0%

Chapman PB et al. NEJM 364;26 June 30, 2011

Hauschild A et al, Lancet 2012 Jul 28;380(9839):358-65

Summary 50-60% of metastatic melanomas harbor V600 BRAF

mutation that leads to constitutive activation of MAPK

pathway

Vemurafenib and dabrafenib are effective BRAF inhibitors

with a response rate of approximately 50% (by RECIST), but

eventually tumors develop resistance to the therapy

The treatment is associated with unique side effects and

dose reduction or interruption is often required

BRAFi vs. MEKi in BRAF-mutant melanoma

• BRAF inhibitors appear to have higher response rates and longer PFS than trametinib

• Both classes of drug have shown survival advantage over chemotherapy in randomized phase III studies.

• Patients whose disease progresses on a prior selective RAF inhibitor do not respond to trametinib alone*

– 0% confirmed response rate among 40 patients in phase II study

• Trametinib can be useful as an alternate to a selective RAF inhibitor when pts cannot tolerate a RAF inhibitor.

• Combination of RAF inhibitor and MEK inhibitor can overcome BRAFi resistance?

*Kim, Kefford, Pavlick et al. SMR meeting 2011

However, Trametinib not effective in patients who

had prior BRAFi Tx

Confirmed Response Rate (RR):

0 response, 11 SD

* Discontinued prior BRAFi due to toxicity

K V600K

Scans unavailable for 5 patients: 2 died and 1 withdrew before first scan,

2 had incomplete scan

M1c M1a M1b M-Stage at screening

266% 155%

K K

K

*

Ch

an

ge

at

ma

xim

um

re

du

cti

on

fro

m

ba

se

lin

e m

ea

su

rem

en

t (%

)

*

*

Kim, Kefford, Pavlick et al. J Clin Oncol. 2013

(n = 40) K

Best percentage change from baseline and best overall response (NRAS)

*Patients with missing best % change from baseline and unknown overall response are not included.

N=28* Progressive Disease (PD)

Stable Disease (SD)

Partial Response (PR)

Unconfirmed PR

45 mg NRAS

Ongoing pts

Ascierto, Berking, Agarwala et al. ASCO 2012

Response rate: 21% (6 of 28 pts) 3 confirmed PR Disease control rate: 68%

Do MEK inhibitors have a role as single agents?

(Kim)

• BRAF-mutant melanomas? (Yes, for proportions of patients) – OS / PFS advantage over chemotherapy

– Lower response rates than BRAF inhibitors

– Alternate treatment option for BRAFi-intolerant patients

– Likely more useful as combination with BRAF inhibitors

• NRAS-mutant melanomas? (Potential, but not optimal) – Potential benefit as a single agent; Need larger trials to confirm.

– Durable clinical benefit less likely as single agents

– A number of combination trials at works (+CDK4i / + AKTi, etc.)

• BRAF/NRAS- Wild type melanomas? (???) – A limited clinical data, but less likely be useful as single agent

• GNAQ/GNA11-mutant (uveal) melanomas? (???) – Await the results of phase II study of Selumetinib vs. Temozolomide

Part C Overall Survival

Time since randomization (months)

1.0

0.8

0.6

0.4

0.2

0.0

0 3 6 9 12 15 18

Estim

ate

d s

urv

iva

l fu

nctio

n

Patients at risk

54 54 50 44 28 4

54 52 46 43 27 3

54 54 52 47 31 7

43/54 (80%) Monotherapy D crossed to 150/2

Median HR, P-

Value

Mono D NR

150/1 NR 0.98, NS

150/2 NR 0.67, NS

12 mo. OS

rate

70%

68%

79%

Med follow up time 14 mo

Long et al., ESMO 2012, Flaherty, K. et al NEJM 2012

BRIM7 Results: Change in tumor size from baseline to

best response in BRAFi-naïve patients

SLD, sum of longest diameters

-30

% C

hange fro

m B

aselin

e in S

LD

of T

arg

et

Lesio

ns

-100

-50

0

50

100

Individual Patients Treated with Vemurafenib and GDC-0973

Best Tumor Response for Each Patient (BRAFi-naïve)

Cohort 1A

Cohort 1B

Cohort 1C

Cohort 2A

Cohort 4

Exp. Cohort 1A

Exp. Cohort 1B

n=25 evaluable patients

Gonzalez, R. et al ESMO 2012

Phase III Study Design (Hersh)

1:1 randomization stratified by: • metastatic stage (M1a, M1b, and M1c) • region (Australia, North America, Western Europe) • baseline LDH (< 0.8 x ULN, 0.8–1.1 x ULN, >1.1-2 x ULN)

Planned N = 514 Chemo-naïve ECOG PS 0-1 Stage IV cutaneous Measurable disease LDH levels ≤2.0 x ULN No current brain mets

nab-Paclitaxel (nab-P) 150 mg/m2 IV

days 1, 8, and 15, 28-day cycle

Dacarbazine (DTIC) 1000 mg/m2 IV, day 1, 21-day cycle

• CT scan every 8 weeks in both arms • Enrollment period April 2009 – June 2011; Data cut-off – June 30, 2012 • Treatment until disease progression or unacceptable toxicity, patient/investigator discretion

ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; ULN, upper limit of normal

N/Events Median PFS (mo) 95% CI

264/152 4.8 3.7 - 5.5

265/170 2.5 2.0 - 3.6

nab-Paclitaxel

Dacarbazine

Pro

bab

ilit

y o

f P

rog

ress

ion

-fre

e S

urv

iva

l

0.00

0.25

0.50

0.75

1.00

0 3 6 9 12 15 18 21 24 27 30 33

HR = 0.792 95.1% CI (0.631 - 0.992)

P = 0.044

PFS by Independent Radiology Review

36

nab-Paclitaxel Dacarbazine

264 265

128 95

49 42

26 31

9 17

5 11

2 6

1 3

1 2

0 1

0 1

0 1

0 0

Months

# at

Ris

k

CI, confidence interval

N/Events* Median OS (mo) 95% CI

264/162 12.8 11.3 - 14.6

265/176 10.7 9.6 - 12.5

nab-Paclitaxel

Dacarbazine

Pro

bab

ilit

y o

f S

urv

ival

HR = 0.831 99.9% CI (0.578 - 1.196)

P = 0.094

OS: Planned Interim Analysis

nab-Paclitaxel Dacarbazine

264 265

240 228

195 184

165 144

128 110

81 80

46 44

28 28

19 18

10 10

4 6

1 2

0 0

0.00

0.25

0.50

0.75

1.00

0 3 6 9 12 15 18 21 24 27 30 33 36

Months

#. a

t R

isk

* At the time of PFS analysis, 64% of patients had an event

Acral Lentiginous Melanoma

Sun Induced Melanoma

Melanoma Melanoma differences in Pathology Distribution

20%

11%

44%

25%

69%

EC I EC IIA-IIB EC IIC-III EC IV y Rec.

Melanoma Stage Distribution

USA / AJCC / México (INCan)

N 132 (100 %)

Mutation Detected 42 (31 %)

NO 90 (69 %)

Ruiz et al, 2013

Melanoma BRAF MUTATION IN MEXICAN POPULATION

Mucosal Melanoma

0

10

20

30

40

50

60

70

80

90

100

USA China Mexico

Acral

Others

Mucosal Melanoma

The Fork in the Melanoma Road

BRAF Wild Type BRAF Mutation

IL-2

Ipilimumab

Anti-PD1

BRAF inhibitor

BRAF + MEK

Ipilimumab

Anti-PD1

Courtesy, Vern Sondak, MD

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